Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that results from neoplastic transformation of primitive hematopoietic stem cells. The disease accounts for approximately 7 - 15 % of all leukemias in adults and until recently had limited therapeutic responsiveness to a wide variety of agents. Through cytogenetic, molecular and biochemical studies the mechanisms associated with initiation CML cell transformation are becoming more clearly understood. In > 95 % of CML patients a reciprocal translocation of chromosomes 9 and 22 result in expression of a chimeric gene encoding an unregulated tyrosine kinase activity, termed BCR-ABL. Numerous animal studies demonstrated that BCR-ABL expression alone was sufficient to induce leukemic-like disorders, suggesting that targeted inhibition of this kinase would provide therapeutic activity in CML. The Novartis drug, Imatinib mesylate (IM) binds to the ATP binding pocket of BCR-ABL inhibiting its activity. Clinical studies with IM have shown remarkable activity in CML with frequent reports of both hematological and cytogenetic remission. However, patients frequently progress or fail to respond to IM, suggesting resistance mechanisms exist that suppress the efficacy or durability of this drug. Clinical studies suggest that point mutations and amplification of the BCR-ABL gene exist and correlate with IM resistance in about 30 to 40 % of CML patients. Analysis of CML cell models and clinical samples suggest that escape from BCR-ABL dependence may account for resistance in other patients. The goal of this project is to fully characterize BCR-ABL dependent and independent mechanisms of IM resistance in CML patients using several techniques including studies of gene mutations, alternate signaling pathways and establishment of cells in short and long term culture to study intrinsic resistance profiles from CML patients. These studies have already identified unique mechanisms of IM resistance and have tested activities of novel agents that overcome various mechanisms of IM resistance. These agents are to be tested in vitro and in clinical studies to determine whether IM resistance and disease progression can be eliminated in CML patients.